Allogeneic hematopoietic stem cell transplantation (allo-HSCT) and solid organ transplantation have been widely used in the treatment of hematologic malignancies, certain genetic diseases, acute severe radiation sickness, and a variety of solid organ failures and malignancies. Due to the differences in the major histocompatibility antigen (MHC) between donors and recipients, along with many other known and unknown factors such as the minor histocompatibility antigen (mHA), tissue-specific antigens, and non-immunological factors, host-versus-graft diseases (HVGDs) and graft-versus-host diseases (GVHDs or GVHRs) are inevitable and are one of the most important and fundamental causes of allogeneic tissue graft failure and graft chronic dysfunction (GCD). With the increasing number of patients in urgent need of organ transplants, the lack of donors is increasingly prominent. Both now and in the future, transplant cases in which the MHCs are not fully compatible or are only semi-compatible will become mainstream and constitute the new direction of hematopoietic stem cell transplantation and organ transplantation. The traditional methods for the prevention and treatment of GVHD and HVGD are based on the destruction of the entire immune function in transplant recipients, even at the cost of the loss of graft-versus-leukemia (GVL) and anti-inflammatory functions, implemented by the use of a variety of high-dose immunosuppressants or the removal of all T cells from the graft. There is no doubt that the fundamental method behind any new strategy to prevent the occurrence and development of GVHD and HVGD depends on whether the initial step of T cell activation can be effectively interfered with or inhibited to induce specific immune tolerance, thereby fundamentally curbing the occurrence and development of a “cytokine storm”. Therefore, an ideal and efficient allo-HSCT and organ transplantation should amend or modify the initial reaction of T cells to allogeneic antigens rather than removing all T cells from the body of the transplant recipient or the donor graft. That is, the induction of recipient or donor-specific immune tolerance should target the elimination or inhibition of the recipient or donor T-cell reaction to allogeneic antigens but still retain the normal reaction of T cells to other antigens.
It has been proven that the recipient and donor T cells play a dual role in hematopoietic stem cell transplantation or organ transplantation. In addition to contributing to the engraftment of hematopoietic stem cells or organs and control conditional infections and anti-leukemia effects, they can also be the root cause of GVHD or HVGD. This immune response is accomplished through recognition and activation by T cells. T cell activation requires two signals: T cell receptor signal and co-stimulation signal of cluster of differentiation 28 (CD28). The first signal is regulated by the second signal, resulting in T cell activation, partial activation or anergy. Therefore, inhibiting T cell activation by blocking either the T cell receptor signal or the CD28-mediated co-stimulatory signal is an important strategy for the prevention of HVGD and acute GVHD (aGVHD). The cytotoxic T-lymphocyte antigen 4-Ig (CTLA4-Ig) or B7 antibody-induced specific immune tolerance is primarily used to achieve the goal of preventing HVGD and aGVHD and has been proven effective in a large number of in vivo and in vitro animal experiments. However, the shortcomings of this method are that the duration of the induced immune tolerance is short and that the induced incompetent T cells can be reactivated by other signaling pathways, leading to treatment failure. In addition, the monoclonal antibodies used for blocking are mostly murine, and their immunogenicity will affect the treatment's efficacy.
Therefore, a DNA vaccine with good immune tolerance and therapeutic efficacy for the treatment or the prevention of allogeneic tissue/organ transplant rejection such as GVHD is urgently needed in this field.